The molluscan cardioexcitatory peptide FMRFamide (Phe-Met- Arg-Phe-NH2), together with four structurally similar peptides, constitute a closely related nuclear family which now includes among its membership two tetrapeptides and three heptapeptides. The tetra-and heptapeptides have different phyletic distributions among the molluscs, and have distinctive effects and receptors on muscles and nerves. Antisera to FMRFamide also cross-react widely with antigens in the nerve and endocrine cells of non- molluscan groups, both vertebrate and invertebrate. Some of this immunoreactivity is due to established peptides, but previously unknown peptides have also been discovered. These immunochemical results are manifestations of a large, heterogeneous, widespread, extended peptide family; it is characterized by an amidated C-terminal dipeptide of the form Arg-X-NH2 (where X is an aromatic residue). The first long-term goal of this project is to examine the tissue distributions, actions and physiological roles of the individual FMRFamide-related peptides (FaRPs) making up the model nuclear family in the pulmonate snail, Helix aspersa. The receptors complementary to the FaRPs will be characterized by studying the structure- activity relations (SAR) of these peptides on whole tissues, biochemical mechanisms, and radioligand-receptor binding properties. The variation in the levels and potency of the FaRPs, as a function of the activity state of the snails will also be examined. The second long-term goal is to determine the phyletic distribution, size, and limits of the extended family of FaRPs, and to define its relationship with the nuclear family in molluscs. New extra-molluscan FaRPs will be sought in central nervous extracts of vertebrates and key invertebrates. The effects, of both the nuclear and extended FaRPs, on vertebrate vascular smooth muscle will be tested and the receptors characterized by SAR. The relationship between the nuclear family of FaRPs and the extended family may reside in the homology of their receptors; the similarities between the peptides themselves are probably due to convergence.